A two-locus system with strong epistasis underlies rapid parasite-mediated evolution of host resistance

Parasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen, Pasteuria ramosa, in a natural host population of Daphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome wide association study (GWAS), we built a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Such epistatic effects with strong fitness consequences in host-parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.

A two-locus system with strong epistasis underlies rapid parasite-mediated evolution of host resistance

Parasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen, Pasteuria ramosa, in a natural host population of Daphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome wide association study (GWAS), we obtained a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Applying the model to the dynamics of the field population revealed moderate changes in allele frequencies at the two resistance loci relative to the profound changes observed at the phenotypic level. This apparent discrepancy is explained by strong epistasis and dominance at the two resistance loci, which reduces the effect of selection on alleles at both loci. Such epistatic effects with strong fitness consequences in host-parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.

Mapping of Multiple Complementary Sex Determination Loci in a Parasitoid Wasp

Sex determination has evolved in a variety of ways and can depend on environmental and genetic signals. A widespread form of genetic sex determination is haplodiploidy, where unfertilized, haploid eggs develop into males and fertilized diploid eggs into females. One of the molecular mechanisms underlying haplodiploidy in Hymenoptera, the large insect order comprising ants, bees, and wasps, is complementary sex determination (CSD). In species with CSD, heterozygosity at one or several loci induces female development. Here, we identify the genomic regions putatively underlying multilocus CSD in the parasitoid wasp Lysiphlebus fabarum using restriction-site associated DNA sequencing. By analyzing segregation patterns at polymorphic sites among 331 diploid males and females, we identify up to four CSD candidate regions, all on different chromosomes. None of the candidate regions feature evidence for homology with the csd gene from the honey bee, the only species in which CSD has been characterized, suggesting that CSD in L. fabarum is regulated via a novel molecular mechanism. Moreover, no homology is shared between the candidate loci, in contrast to the idea that multilocus CSD should emerge from duplications of an ancestral single-locus system. Taken together, our results suggest that the molecular mechanisms underlying CSD in Hymenoptera are not conserved between species, raising the question as to whether CSD may have evolved multiple times independently in the group.

Population Genetics of the Highly Polymorphic RPP8 Gene Family

Plant nucleotide-binding domain and leucine-rich repeat containing (NLR) genes provide some of the most extreme examples of polymorphism in eukaryotic genomes, rivalling even the vertebrate major histocompatibility complex. Surprisingly, this is also true in Arabidopsis thaliana, a predominantly selfing species with low heterozygosity. Here, we investigate how gene duplication and intergenic exchange contribute to this extraordinary variation. RPP8 is a three-locus system that is configured chromosomally as either a direct-repeat tandem duplication or as a single copy locus, plus a locus 2 Mb distant. We sequenced 48 RPP8 alleles from 37 accessions of A. thaliana and 12 RPP8 alleles from Arabidopsis lyrata to investigate the patterns of interlocus shared variation. The tandem duplicates display fixed differences and share less variation with each other than either shares with the distant paralog. A high level of shared polymorphism among alleles at one of the tandem duplicates, the single-copy locus and the distal locus, must involve both classical crossing over and intergenic gene conversion. Despite these polymorphism-enhancing mechanisms, the observed nucleotide diversity could not be replicated under neutral forward-in-time simulations. Only by adding balancing selection to the simulations do they approach the level of polymorphism observed at RPP8. In this NLR gene triad, genetic architecture, gene function and selection all combine to generate diversity.

Population genetics of the highly polymorphicRPP8gene family

Plant NLR resistance genes provide some of the most extreme examples of polymorphism in eukaryotic genomes, rivalling even the vertebrate major histocompatibility complex. Surprisingly, this is also true inArabidopsis thaliana, a predominantly selfing species with low heterozygosity. Here, we investigate how gene duplication and intergenic exchange contribute to this extraordinary variation.RPP8is a three-locus system that is configured chromosomally as either a direct-repeat tandem duplication or as a single copy locus, plus a locus 2 Mb distant. We sequenced 48RPP8alleles from 37 accessions ofA. thalianaand 12RPP8alleles fromA. lyratato investigate the patterns of interlocus shared variation. The tandem duplicates display fixed differences and share less variation with each other than either shares with the distant paralog. A high level of shared polymorphism among alleles at one of the tandem duplicates, the single-copy locus and the distal locus, must involve both classical crossing over and intergenic gene conversion. Despite these polymorphism-enhancing mechanisms, the observed nucleotide diversity could not be replicated under neutral forward-in-time simulations. Only by adding balancing selection to the simulations do they approach level of polymorphism observed atRPP8. In this NLR gene triad, genetic architecture, gene function and selection all combine to generate diversity.

Estimating the timing of multiple admixture events using 3-locus Linkage Disequilibrium

Estimating admixture histories is crucial for understanding the genetic diversity we see in present-day populations. Existing allele frequency or phylogeny-based methods are excellent for inferring the existence of admixture or its proportions, but have less power for estimating admixture times. Recently introduced approaches for estimating these times use spatial information from admixed chromosomes, such as the local ancestry or the decay of admixture linkage disequilibrium (ALD). One popular method, implemented in the programs ALDER and ROLLOFF, uses two-locus ALD to infer the time of a single admixture event, but is only able to estimate the time of the most recent admixture event based on this summary statistic. We derive analytical expressions for the expected ALD in a three-locus system and provide a new statistical method based on these results that is able to resolve more complicated admixture histories. Using simulations, we show how this new statistic behaves on a range of admixture histories. As an example, we also apply our method to the Colombian and Mexican samples from the 1000 Genomes project.

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem

Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. A complete derivation of this relationship from a general disease model is shown for very large sample sizes. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non-interrogated causal site using data at closely linked markers. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods.